Mixed carboxylato platinum (II) complexes

ABSTRACT

Novel platinum(II) carboxylatocomplexes of the following general formula: ##STR1## wherein R is tetrahydrofurfuryl or cyclo-C n  R&#34; 2n-1 , R&#34; is H, an alkyl, hydroxyl, n=3-6; R&#39; is --CH 2  --, --CH 2  --CH 2  --, --CH(OH)--, --CH(OH)--CH 2  --, --CH(OH)--CH(OH)--. 
     These compounds possess a clearly pronounced antitumor activity and are readily soluble in water. 
     A process for preparing these compounds comprises reacting K [PtCl 3  NH 3  ] with KI, followed by treatment of the reaction mixture with tetrahydrofurfurylamine or an alicyclic amine and treatment of the resulting mixture of complexes with a silver salt of the formula: Ag 2  (OOC--R&#39;--COO), wherein R&#39; is as identified above.

FIELD OF THE INVENTION

The present invention relates to complex platinum compounds and, morespecifically, to mixed carboxylate platinum(II) complexes and to aprocess for preparing same.

Mixed carboxylate platinum complexes are biologically active compoundswhich exhibit antitumor activity.

BACKGROUND OF THE INVENTION

Known in the art is a complex platinum compound, viz.cis-dichlorodiamine platinum(II) (DDP) (Nature; vol. 222, 1969(Macmillan (Journals) LTD, London) B. Rosenberg, L. Van Camp, J. E.Trosko, V. H. Mansour: "Platinum Compounds; A New Class of AntitumorAgents", p. 385).

This platinum compound has the formula: ##STR2## and reveals a highantitumor activity.

It possesses a remarkably wide spectrum of action on diverse tumors,activity in respect of rapidly growing and slowly developing neoplasms,as well as activity in respect of not only early-formed (small-size)neoplasms but also in respect of well-formed and even far-gone anddisseminated neoplasms; it is also characterized by the absence oftypical specificity.

Nevertheless, likewise all antitumor compounds, in addition to theeffect on neoplasms, DDP exhibits a toxic effect the organism, thuslimiting dosage of this compound and frequently forcing discontinuationof the treatment due to a toxic effect of the compound on kidney. TheLD₅₀ of this platinum complex (the dose at which 50% of the test animalsare dead) is the same for mice and rats--about 13 mg/kg (Vestnik AMNSSSR, No. 2, 1979 (Medicina, Moscow); M. A. Presnov, A. L. Konovalova,V. P. Koral'chuk "Complex Compounds of Platinum in Chemotherapy ofMalignant Tumors", p. 72).

Furthermore, an insufficient solubility of DDP in water (0.25 mass % at25° C.) complicates the use of this preparation in clinics and makes itimpossible to carry out a local treatment of the tumor with a solutioncontaining a high concentration of the preparation.

Also known in the art are platinum(II) dichlorocomplexes with twomolecules of primary alicyclic amines, beginning with cyclopropylamineand ending with cyclooctylamine also revealing antitumor properties andcorresponding to the formula: ##STR3## wherein n is 1 to 6 (Chem.-Biol.Interaction, vol. 5, 1972, Elsevier, Netherlands): T. A. Connors, M.Jones, W. C. J. Ross, P. D. Braddock, A. R. Khokhar, M. L. Tobe "Newplatinum complexes with antitumor activity", see p. 421-422).Chem.-Biol. Interaction, vol. 11, 1975 (Elsevier, Netherlands): P. D.Braddock, T. A. Connors, M. Jones, A. R. Khokhar, D. H. Melzack, M. L.Tobe "Structure and activity relationships of platinum complexes withantitumor activity", p. 153).

On regrafted plasmacytoma of mice ADJ/PC6A these complexes show a highantitumor activity, the highest selectivity of their action is observedfor complexes with cyclopentyl- and cyclohexylamine (therapeuticalindexes (TI/equal to the ratio of the LD₅₀ to the inhibiting dose (ID)suppressing growth of the tumor by 90%, TI=LD₅₀ /ID₉₀ are equal to 200and above 267 respectively). These very high therapeutical index valueshave caused clinical tests of cis-[PtCl₂ (cyclo-C₅ H₉ NH₂)₂ ] (cf.Cancer Treatment Reports, vol. 63, No. 9-10, September-October 1979(national Cancer Institute, Bethesda); J. M. Hill, E. Loeb, A. Pardue,A. Khan, J. J. King, C. Aleman, N. O. Hill "Platinum Analogs of ClinicalInterest", see p. 1510, 1512).

This compound, however, is substantially insoluble in water, whereforeit should be administered in the form of fine suspensions in sesame oilor in the form of aqueous solloids stabilized by polyvinylpyrrolidone.The administration of the compound in these forms has shown that itsubstantially remains at the spot of the injection and no therapeuticresponse or a side effect, apart from a local irritation uponadministration of an oily suspension, is observed, wherefore furthertests were stopped.

Known in the art is also a mixed chloride platinum(II) complexcontaining ammonia and cyclopentylamine having formula: cis-[PtCl₂ NH₃(cyclo-C₅ H₉ NH₂)] (cf. British Pat. No. 2,060,615A Cl. C 07 F 15/00, A61 K 31/555 published in 1981).

Tests of the compound on a regrafted plasmacytoma of mice ADJ/PC6A haveshown that the compound is slightly more toxic than DDP (LD₅₀ are 11.0and 13.0 mg/kg respectively), but it inhibits growth of tumors by 90% ina dose which is by 3 times as less as that of DDP and nearly 5 times asless as that of cis-[PtCl₂ (cyclo-C₅ H₉ NH₂)₂ ]/ID₉₀ is equal to 0.5,1.6 and 2.4 mg/kg respectively).

However, in the paper (Cancer Treatment Reports, vol. 63, No. 9-10,September-October, 1979 (National Cancer Institute, Bethesda): T. A.Connors, M. J. Cleare, K. R. Harrap "Structure-Activity Relationships ofthe Antitumor Platinum Coordination Complexes", see p. 1501) aconclusion is made to the effect of absence of advantages of this mixedcomplex as compared to the parent compounds with identical ligands.

As regards solubility in a 0.9% NaCl (about 1 mg/ml), the mixed platinumcomplex does not differ from DDP (see J. E. Schurig, W. T. Bradner, J.B. Huftalen, G. J. Doyle, J. A. Gylys "Toxic side effects of platinumanalogs" in: A. W. Prestyako, S. T. Crooke (Eds.) Cisplatin CurrentStatus and New Developments", 1980, Academic Press (New York), see p.228, 230).

For the synthesis of this mixed complex of platinum a known method ofsynthesis of such compounds has been used which is based on interactionof the complex K [PtCl₃ (NH₃)] with cyclopentylamine. The yield of thepurified product is 4.8% (see the British Patent referred tohereinabove).

DISCLOSURE OF THE INVENTION

The present invention is directed to the provision of novel mixedplatinum(II) carboxylate complexes which would possess an antitumoractivity and would be soluble in water, as well as to the provision of aprocess for preparing same.

This object has been accomplished by the provision of novel mixedplatinum(II) carboxylato complexes which, according to the presentinvention have the general formula: ##STR4## wherein R istetrahydrofurfuryl or cyclo-C_(n) R"_(2n-1), wherein R" is H, an alkyl,a hydroxyl, n=3 to 6, R' is --CH₂ --, --CH₂ --CH₂ --, --CH(OH)--,--CH(OH)--CH₂ --, --CH(OH)--CH(OH)--.

The compounds according to the present invention possess a considerableantitumor activity on a number of graft strains of turmors and leukosesof mice which is reflected in inhibition of tumor growth and in aconsiderable extension of the life span of animals with leukoses. Thecompounds according to the present invention have an advantage residingin their high solubility in water, a higher antitumor activity and alower toxicity as compared to cis-dichloroammine platinum.

The process for preparing the mixed carboxylato platinum(II) complexesaccording to the present invention consists in the following steps:

(1) interaction of potassium trichloroammineplatinate(II) of the formulaK[PtCl₃ NH₃ ] with potassium iodide in an aqueous medium in a molarratio of 1:4-6;

(2) treatment of the resulting reaction mixture with an amine such astetrahydrofurfurylamine or an amine of the formula: cyclo-C_(n)R"_(2n-1) --NH₂, wherein n=3 to 6, R" is H, an alkyl, a hydroxyl, togive a mixture of platinum complexes cis-[PtIClNH₃ A] and cis-[PtI₂ NH₃A], wherein A is the above-mentioned amine;

(3) interaction of the resulting mixture of platinum complexes with asilver salt of a dicarboxylic acid of the formula: Ag₂ (OOC--R'--COO),wherein R' is --CH₂ --, --CH₂ --CH₂ --, --CH(OH)--, --CH(OH)--CH₂ --,--CH(OH)--CH(OH)-- in an aqueous medium.

The reaction of the components in the stage (1, 2) can be carried out atroom temperature, while the reaction of the components in stage (3)should be preferably carried out at a mild heating to the temperature of45° C.

The reaction of the components in stage (3) should be better conductedat a molar ratio equal or close to the stoichiometric one. This resultsin the preparation of a product of a higher purity grade.

The process according to the present invention can be readilyimplemented on a commercial scale, since it is simple and requires nohigh rates of energy consumption.

From the above-given formula it is seen that in the compounds accordingto the present invention as neutral ligands ammonia andtetrahydrofurfurylamine or an alicyclic amine beginning withcyclopropylamine (n=3) and ending with cyclohexylamine (n=6) are usedwhich are connected to platinum through the nitrogen atom and occupyingtwo cis-positions. As the acid bidentate ligand in the compounds of thisinvention there can be present an anion of malonic acid ⁻ OOC--CH₂--COO⁻, or anion of succinic acid ⁻ OOC--CH₂ --CH₂ --COO⁻, or anions oftheir hydroxy derivatives: anion of hydroxymalonic (tartronic) acid ⁻OOC--CH(OH)--COO⁻ acid, malic acid ⁻ OOC--CH₂ --CH(OH)--COO⁻ or tartaricacid ⁻ OOC--CH(OH)--CH(OH)--COO⁻. The compounds with the moiety of malicacid can exist in the form of two geometric isomers differing in theposition of hydroxy group relative to two different amines(structures/a/ and /b/) ##STR5## wherein R has the meaning as in thegeneral formula hereinabove.

Almost equal amounts of these isomers are formed in the syntheses. Forthe synthesis of complexes with anions of acids containing chiralcenters (malic acid, tartaric acid) both optically activenaturally-occurring forms of these acids (S(-)-malic acid andR,R(+)-tartaric acid) and racemic acids, as well as meso-form oftartaric acid can be used.

The location of neutral ligands in all of the complexes in thecis-position relative to one another follows from the procedure of theirsynthesis and is justified by the bidentatic coordination of moieties ofdicarboxylic acids forming six- or seven-membered cycles. Chelate cyclesof this size can terminate only cis-positions in the complex. Thebidentate coordination of moieties of dicarboxylic acids in thecompounds is proven by the presence, in their IR-spectra, of bandscorresponding to oscillations of deprotonized coordinated groups --COO⁻(in the region of 1,600 cm⁻¹).

The compounds according to the present invention comprise fine-crystalpowders of white or greyish-white powder extremely well soluble inwater, a physiological solution of NaCl, in aqueous solutions of glucose(solubility of the complexes is above 200 mg per ml). This highsolubility in water is unusual for non-electrolyte complexes ofplatinum(II) containing no acid groups readily substituted with water orside fragments ionized in solution which represent a valuable propertyof the compounds according to the present invention. The compounds arestable in storage in dark places at a temperature within the range offrom +5° to 0° C. (in a refrigerator).

The compounds according to the present invention can be exemplified by:malonatoammine(cyclopropylamine)platinum(II),malonatoammine(cyclobutylamine)platinum(II),(hydroxymalonato)ammine(cyclobutylamine)platinum(II),malonatoammine(cyclopentylamine)platinum(II),(hydroxymalonato)ammine(cyclopentylamine)platinum(II),S(-)malatoammine(cyclopentylamine)platinum(II),RS-malatoammine(cyclopentylamine)platinum(II),R,R(+)-tartratoammine(cyclopentylamine)platinum(II),racem-tartratoammine(cyclopentylamine)platinum(II),meso-tar-tratoammine(cyclopentylamine)platinum(II),succinatoammine(cyclopentylamine)platinum(II),malonatoammine(cyclohexylamine)platinum(II),(hydroxymalonato)ammine(cyclohexylamine)platinum(II),S(-)-malatoammine(cyclohexylamine)platinum(II),succinatoammine(cyclohexylamine)platinum(II),S(-)-malatoammine(2-methylcyclohexylamine)platinum(II),S(-)-malatoammine(3-methylcyclohexylamine)platinum(II),S(-)-malatoammine(4-methylcyclohexylamine)platinum(II),S(-)-malatoammine (4-hydroxycyclohexylamine)platinum(II),malonatoammine(tetrahydrofurfurylamine)platinum(II),S(-)-malatoammine(tetrahydrofurfurylamine)platinum(II).

The synthesis of the compounds by the process according to the presentinvention can be represented by the following scheme: ##STR6## wherein Ris tetrahydrofurfuryl or cyclo-C_(n) R"_(2n-1), where R" is H, an alkyl,hydroxy, n=3-6, R' is --CH₂, --CH₂ --CH₂ --, --CH(OH)--, --CH(OH)--CH₂--, --CH(OH)--CH(OH)--.

In the first stage of the synthesis potassiumtrichloroammineplatinate(II) K[PtCl₃ NH₃ ] is reacted in an aqueousmedium with potassium iodide in a molar ratio of 1:(4-6).

Then the resulting reaction mixture is treated with the above-specifiedamine to yield a yellow-brown mixture of diiodo- and iodochlorocomplexescis-[PtI₂ NH₃ (R--NH₂)] and cis-[PtClINH₃ (R--NH₂)] in a yield of75-90%. At a molar ratio of K[PtCl₃ NH₃ ]:KI above or below theabove-specified value in the stage (I) the intermediate mixture ofdiiodo- and iodo-chlorocomplexes obtained in the stage (2) becomesstrongly contaminated with by-products. The resulting mixture ofcomplexes is reacted with the above-mentioned silver salt.

On completion of the reaction the mixture of AgCl and AgI is separatedby filtration, the filtrate is thickened by evaporation in vacuum andthe desired compound is precipitated by an alcohol, acetone or any othersuitable organic solvent. The process according to the present inventionmakes it possible to produce the desired compounds with a sufficientpurity and a good yield (up to 70% as calculated for the startingK[PtCl₃ NH₃ ]).

All the reactants employed in the process according to the presentinvention are well known substances which are readily available.

BEST MODE FOR CARRYING OUT THE INVENTION

The highest antitumor activity among the compounds according to thepresent invention is exhibited byS(-)-malatoammine(cyclopentylamine)platinum(II) [Pt(S(-)-OOCCH(OH)CH₂COO)NH₃ (cyclo-C₅ H₉ NH₂)].0.5H₂ O.

This compound is prepared by reacting K[PtCl₃ NH₃ ] with KI in anaqueous medium at the molar ratio of 1:4.5.

Then the resulting reaction mixture is treated with cyclopentylamine togive a mixture of complexes of platinum: cis-[PtI₂ NH₃ (cyclo-C₅ H₉NH₂)] and cis-[PtIClNH₃ (cyclo-C₅ H₉ NH₂)]. Then the thus-obtainedmixture of platinum complexes is reacted in an aqueous medium withsilver S(-)-malate at the molar ratio of 1:1. After separation of therecovered silver halides and thickening of the filtrate in vacuum thefinal product is isolated by precipitation with acetone.

When used in optimal doses,S(-)-malatoammine(cyclopentylamine)platinum(II) ensures curing of up to100% of animals with plasmacytoma MOPC-406 and up to 66% of animals withhepatoma 22a; it also provides for the most significant extension oflife span of animals with leukemia L-1210 and hemocytoblastosis La (195and 113% respectively).

For a better understanding of the present invention, some specificexamples illustrating preparation of the compounds, their properties andutility are given hereinbelow.

EXAMPLE 1 Preparation of malonatoammine(cyclopropylamine)platinum(II)[Pt(OOCCH₂ COO)NH₃ (cyclo-C₃ H₅ NH₂)]

To a solution of 9.00 g of K[PtCl₃ NH₃ ] (25.2 mmol) in 60 ml of water20.9 g of KI are added (126 mmol; molar ratio 1:5). The solution is keptin darkness for 30 minutes and added under stirring with 1.72 g ofcyclopropylamine in 3 ml of water (30.1 mmol; excess 25%). The formedyellow precipitate is filtered-off, washed with a diluted hydrochloricacid and then with water. The compound is dried in darkness in avacuum-desiccator over P₂ O₅. As a result, a mixture of complexescis-[PtIClNH₃ (cyclo-C₃ H₅ NH₂)] and cis-[PtI₂ NH₃ (cyclo-C₃ H₅ NH₂)] isobtained with the yield of 9.56 g. The content of platinum is 41.3%, theyield for platinum is 80%.

To a suspension of 4.50 g of the resulting mixture of platinum complexes(9.53 mmol) in about 100 ml of water 3.03 g of silver malonate (9.53mmol) are added. The mixture is stirred in darkness at room temperaturefor 4 hours till a complete coagulation of silver halides. Theprecipitate consisting of AgCl and AgI is filtered-off, the filtrate ismixed with activated coal and, after the removal of coal, the filtrateis evaporated in vacuum to a small volume. The compound is isolated bysettling from an aqueous solution with ethanol. To recover the compound,it is also possible to use acetone and mixtures of alcohol or acetonewith ether purified from peroxides. The recovered white substance iswashed with ethanol, dried in a vacuum desiccator at the temperature of60° C. over P₂ O₅. The product yield is 2.56 g (76% of the theoreticalvalue as calculated for the employed mixture of dihalocomplexes; 60% ascalculated for K[PtCl₃ NH₃ ].

Found, %: Pt 52.3, N 7.5, C 18.5, H 3.6. C₆ H₁₂ N₂ O₄ Pt. Calculated, %:Pt 52.4, N 7.5, C 19.35, H 3.25.

EXAMPLE 2 Preparation of malonatoammine(cyclobutylamine)platinum(II)[Pt(OOCCH₂ COO)NH₃ (cyclo-C₄ H₇ NH₂)]

To a solution of 3.52 g of K[PtCl₃ NH₃ ] (9.84 mmol) in 25 ml of water8.98 g of KI (54.1 mmol, molar ratio is 1:5.5) are added. The solutionis kept in darkness for 25 minutes, added under stirring with 0.77 g ofcyclobutylamine in 3 ml of water (10.8 mmol; excess 10%). The formedbrownish-yellow precipitate is filtered-off, washed with a dilutedhydrochloric acid and then with water. The compound is dried in darknessin a vacuum desiccator over P₂ O₅ to give a mixture of complexes:cis-[Pt-IClNH₃ (cyclo-C₄ H₉ NH₂)] and cis-[PtI₂ NH₃ (cyclo-C₄ H₉ NH₂)].The yield is 3.73 g of the mixture of halocomplexes with the content ofplatinum of 40.8%, the yield based on platinum is 79%.

To a suspension of 3.64 g of the resulting mixture of complexes (7.62mmol) in 80 ml 2.42 g of silver malonate (7.62 mmol) are added. Themixture is stirred for 5 hours in darkness at room temperature till acomplete coagulation of silver halides. The precipitate consisting ofAgCl and AgI is filtered-off, the filtrate is mixed with activatedcarbon, and after separation of carbon by filtration, evaporated invacuum to the volume of about 10 ml. The product is separated from theaqueous solution by precipitation with acetone, filtered off, washedwith acetone and ether. The resulting white substance is dried in avacuum desiccator over P₂ O₅. The yield is 2.23 g (76% as calculated forthe employed mixture of dihalocomplexes; 60% as calculated for K[PtCl₃NH₃ ].

Found, %: Pt 50.8, N 7.3, C 21.5, H 3.8. C₇ H₁₄ N₂ O₄ Pt. Calculated, %:Pt 50.6, N 7.3, C 21.8, H 3.7.

EXAMPLE 3 Preparation of(hydroxymalonato)ammine(cyclobutylamine)platinum(II)[Pt(OOCCH(OH)COO)NH₃ (cyclo-C₄ H₇ NH₂)]

This complex is prepared in a manner similar to that described for thecompound of Example 2 hereinabove. Silver hydroxymalonate is enteredinto an exchange reaction with a mixture of platinum dihalocomplexes.The compound is isolated from the aqueous solution by precipitation withan alcohol or acetone or by crystallization directly from theconcentrated solution upon cooling. The yield is 75% as calculated forthe employed mixture of dihalocomplexes; 59% as calculated for K[PtCl₃NH₃ ].

Found, %: Pt 48.8, N 6.8, C 21.1, H 3.7. C₇ H₁₄ N₂ O₅ Pt. Calculated, %:Pt 48.6, N 7.0, C 20.95, H 3.5.

EXAMPLE 4 Preparation of S(-)malatoammine(cyclopentylamine)platinum(II)[Pt(S(-)-OOCCH(OH)CH₂ COO)NH₃ (cyclo-C₅ H₉ NH₂)].0.5H₂ O

To a solution of 8.00 g of K[PtCl₃ NH₃ ] (22.4 mmol) in about 50 ml ofwater 16.71 g of KI (100.8 mmol, molar ratio of 1:4.5) are added. Thesolution is kept in darkness for 20 minutes and added under stirringwith 2.29 g (26.9 mmol, excess 20%) of cyclopentylamine in 5 ml ofwater. The reaction mixture is stirred for 5 minutes. The resultingbrownish-yellow precipitate is filtered-off, washed with a dilutedhydrochloric acid and water, dried in a vacuum desiccator over P₂ O₅ togive a mixture of cis-[PtIClNH₃ (cyclo-C₅ H₉ NH₂)] and cis-[PtI₂ NH₃(cyclo-C₅ H₉ NH₂)]. The yield of the mixture of these complexes is 9.94g, the content of platinum is 38.7%, the yield as calculated forplatinum is 88%.

To a suspension of 4.50 g of the resulting mixture of dihalocomplexes ofplatinum (8.93 mmol) in about 100 ml of water 3.11 g of silverS(-)-malate (8.93 mmol) are added. The mixture is stirred in darkness atroom temperature for 5 hours to ensure a complete coagulation of silverhalides.

After filtering-off the precipitate of silver halides, the filtrate isstirred with activated carbon, the latter is removed by filtration andthe filtrate is evaporated in vacuum to the volume of about 10 ml. Thecompound is settled by addition of acetone, the residue is filtered-off,washed with acetone and dry ether containing no peroxides andimmediately afterwards it is placed into a vacuum desiccator to be driedover P₂ O₅.

The compound is hydroscopic, the combined water is not fully removedeven after a long-time drying over P₂ O₅. The yield of the driedcompound is 2.84 g (72.7% as calculated for the mixture ofdihalocomplexes, 64% as clalculated for K[PtCl₃ NH₃ ].

Found, %: Pt 44.6, N 6.5, C 24.9, H 4.5. C₉ H₁₉ N₂ O₅.5 Pt. Calculated,%: Pt 44.5, N 6.4, C 24.7, H 4.4.

EXAMPLE 5 Preparation of RS-malatoammine(cyclopentylamine)platinum(II)[Pt(RS-OOCCH(OH)CH₂ COO)NH₃ (cyclo-C₅ H₉ NH₂)].0.5H₂ O

The synthesis of this compound is carried out in a manner similar tothat for the compound described in Example 4 hereinabove, except that asthe reactant use is made of a silver salt of racemic malic acid.

The subsequent operations are performed according to the procedure ofthe foregoing Example 4.

The product yield is 49% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 44.3, N 6.2, C 25.1, H 4.7. C₉ H₁₉ N₂ O₅.5 Pt. Calculated,%: Pt 44.5, N 6.4, C 24.7, H 4.4.

EXAMPLE 6 Preparation of malonatoammine(cyclopentylamine)platinum(II)[Pt(OOCCH₂ COO)NH₃ (cyclo-C₅ H₉ NH₂)]

The preparation of this complex is effected in a manner similar to thatdescribed for the synthesis of the compound of Example 4 hereinabefore.2.52 g of silver malonate (7.93 mmol) are entered into an exchangereaction with 4.00 g of mixture of dihalocomplexes cis-[PtI₂ NH₃(cyclo-C₅ H₉ NH₂)] and cis-[PtIClNH₃ (cyclo-C₅ H₉ NH₂)] (7.93 mmol) in70 ml of water. The mixture is stirred in darkness upon heating to thetemperature of 45° C. for 4 hours till a complete coagulation of silverhalides. The filtrate after separation of silver halides is mixed withactivated carbon, the latter is separated by filtration, the filtrate isevaporated in vacuum till the formation of a viscous solution, theresidual water is removed by a three-time evaporation in vacuum withabsolute ethanol and the compound is precipitated by the addition ofacetone. The formed white precipitate is washed with acetone and dryether containing no peroxides. The substance is immediately placed intoa vacuum desiccator and dried over P₂ O₅, since the wet substance isvery hygroscopic. The yield of the dried substance is 2.49 g (81% ascalculated for the employed mixture of dihalocomplexes; 71% ascalculated for K[PtCl₃ NH₃ ]).

Found, %: Pt 49.0, N 7.3, C 23.9, H 4.1. C₈ H₁₆ N₂ O₄ Pt. Calculated, %:Pt 48.7, N 7.0, C 24.0, H 4.0.

EXAMPLE 7 Preparation of(hydroxymalonato)ammine(cyclopentylamine)platinum(II)[Pt(OOCCH(OH)COONH₃ (cyclo-C₅ H₉ NH₂)]

The preparation of this compound is carried out in a manner similar tothe synthesis of the compound described in Example 4 hereinbefore.Silver hydroxymalonate is entered into an exchange reaction with amixture of platinum dihalocomplexes. After separation of silverdihalides and treatment of the reaction mixture with activated carbonthe compound is isolated from a concentrated aqueous solution byprecipitation with acetone and ether.

The product yield is 63% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 47.2, N 6.6, C 23.0, H 3.6. C₈ H₁₆ N₂ O₅ Pt. Calculated, %:Pt 47.0, N 6.8, C 23.1, H 3.9.

EXAMPLE 8 Preparation ofR,R(+)-tartratoammine(cyclopentylamine)platinum(II)[Pt(R,R(+)-OOCCH(OH)CH(OH)COO)NH₃ (cyclo-C₅ H₉ NH₂)].H₂ O

The preparation of this compound is conducted in a manner similar to thesynthesis of the compound described in Example 4. Into an exchangereaction with a mixture of platinum dihalocomplexes silverR,R(+)-tartrate is entered.

The product yield is 57% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 41.8, N 6.0, C 23.6, H 4.5. C₉ H₂₀ N₂ O₇ Pt. Calculated, %:Pt 42.1, N 6.1, C 23.3, H 4.4.

EXAMPLE 9 Preparation ofracem.-tartratoammine(cyclopentylamine)platinum(II)[Pt(racem.-OOCCH(OH)CH(OH)COO)NH₃ (cyclo-C₅ H₉ NH₂)].H₂ O

The preparation of this compound is carried out in a manner similar tothe synthesis of the compound described in Example 4 hereinbefore. Asilver salt of racemic tartaric acid is entered into an exchangereaction with a mixture of platinum dihalocomplexes. The product yieldis 52% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 41.7, N 6.0, C 23.7, H 4.6. C₉ H₂₀ N₂ O₇ Pt. Calculated, %:Pt 42.1, N 6.1, C 23.3, H 4.4.

EXAMPLE 10 Preparation ofmeso-tartratoammine(cyclopentylamine)platinum(II)[Pt(meso-OOCCH(OH)CH(OH)COO)NH₃ (cyclo-C₅ H₉ NH₂)].H₂ O

The preparation of this compound is carried out in a manner similar tothe synthesis of the compound described in Example 4. A silver salt ofmeso-tartaric acid is entered into a reaction of exchange with a mixtureof platinum dihalocomplexes.

The product yield is 61% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 41.9, N 6.1, C 23.5, H 4.7. C₉ H₂₀ O₇ Pt. Calculated, %: Pt42.1, N 6.1, C 23.3, H 4.4.

EXAMPLE 11 Preparation of succinatoammine(cyclopentylamine)platinum(II)[Pt(OOCCH₂ CH₂ COO)NH₃ (cyclo-C₅ H₉ NH₂)]

The preparation of this compound is carried out in a manner similar tothe synthesis of the compound described in Example 4 hereinbefore.Silver succinate is entered into an exchange reaction with a mixture ofplatinum dihalocomplexes.

The product yield is 69% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 47.0, N 6.6, C 26.4, H 4.5. C₉ H₁₈ N₂ O₄ Pt. Calculated, %:Pt 47.2, N 6.8, C 26.2, H 4.4.

EXAMPLE 12 Preparation of malonatoammine(cyclohexylamine)platinum(II)[Pt(OOCCH₂ COO)NH₃ (cyclo-C₆ H₁₁ NH₂)]

To a solution of 3.00 g of K[PtCl₃ NH₃ ] (8.39 mmol) in 20 ml of water5.57 g of KI (33.6 mmol, molar ratio 1:4) are added. The solution iskept in darkness for 20 minutes, then added under stirring with 1.16 g(11.7 mmol) of cyclohexylamine in 5 ml of water. The reaction mixture isstirred for 5 minutes. The formed brownish-yellow precipitate isfiltered-off, washed with a diluted hydrochloric acid and water, driedin a vacuum desiccator over P₂ O₅. As a result, a mixture ofcis-[PtClINH₃ (cyclo-C₅ H₉ NH₂)] and cis-[PtI₂ NH₃ (cyclo-C₅ H₉ NH₂)] isobtained. The yield of the mixture is 3.79 g, the content of platinum inthis mixture of complexes is 39.7%; the yield as calculated for platinumis 92%.

To a suspension of 3.50 g of the resulting mixture of platinumdihalocomplexes (7.13 mmol) in about 70 ml of water 2.26 g (7.11 mmol)of silver malonate are added. The mixture is stirred in darkness uponheating to the temperature of 40° C. for 7 hours till a completecoagulation of silver halides. After separation of the precipitate ofsilver halides by filtration the filtrate is mixed with activatedcarbon, the latter is removed by filtration and the filtrate isevaporated in vacuum till the formation of a viscous solution. Thecompound is precipitated by the addition of an alcohol and acetone. Theresulting white precipitate is washed with acetone, ether and dried in avacuum desiccator over P₂ O₅.

The product yield is 2.21 g (75% as calculated for the mixture ofdihalocomplexes, 69% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 47.2, N 6.6, C 26.3, H 4.4. C₉ H₁₈ N₂ O₄ Pt. Calculated, %:Pt 47.2, N 6.8, C 26.2, H 4.4.

EXAMPLE 13 Preparation of(hydroxymalonato)ammine(cyclohexylamine)platinum(II)[Pt(OOCCH(OH)COO)NH₃ (cyclo-C₆ H₁₁ NH₂)]

The preparation of this compound and isolation thereof are carried outin a manner similar to that described in the foregoing Example 12.Silver hydroxymalonate is entered into an exchange reaction with amixture of dihalocomplexes.

The product yield is 64% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 45.3, N 6.5, C 25.4, H 4.2 C₉ H₁₈ N₂ O₅ Pt. Calculated, %:Pt 45.4, N 6.5, C 25.2, H 4.2.

EXAMPLE 14 Preparation of S(-)malatoammine(cyclohexylamine)platinum(II)[Pt(S(-)-OOCCH(OH)CH₂ COO)NH₃ (cyclo-C₆ H₁₁ NH₂)].H₂ O

The preparation of this compound and isolation thereof are carried outin a manner similar to that described in Example 12 hereinbefore. SilverS(-)-malate is entered into an exchange reaction with a mixture ofdihalocomplexes.

The product yield is 59% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 42.0, N 6.1, C 26.2, H 5.0. C₁₀ H₂₂ N₂ O₆ Pt. Calculated,%: Pt 42.3, N 6.1, C 26.0, H 4.8.

EXAMPLE 15 Preparation of succinatoammine(cyclohexylamine)platinum(II)[Pt(OOCCH₂ CH₂ COO)NH₃ (cyclo-C₆ H₁₁ NH₂)]

The preparation of this compound is carried out in a manner similar tothe synthesis of the compound described in Example 12 hereinbefore. Intoan exchange reaction with a mixture of dihalocomplexes silver succinateis entered.

The product yield is 69% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 45.5, N 6.7, C 28.0, H 4.9. C₁₀ H₂₀ N₂ O₄ Pt. Calculated,%: Pt 45.7, N 6.6, C 28.1, H 4.7.

EXAMPLE 16 Preparation ofS(-)-malatoammine(2-methylcyclohexylamine)platinum(II)[Pt(S(-)-OOCCH(OH)CH₂ COO)NH₃ (2-CH₃ -cyclo-C₆ H₁₀ NH₂)].0.5H₂ O

To a solution of 4.00 g of K[PtCl₃ NH₃ ] (11.7 mmol) in about 25 ml ofwater 8.36 g of KI (50.4 mmol, molar ratio of 1:4.5) are added. Thesolution is kept in darkness for 20 minutes and added under stirringwith 1.52 g of 2-methylcyclohexylamine (13.4 mmol) in 5 ml of water. Thereaction mixture is stirred for 5 minutes. The resulting brownish-yellowprecipitate is filtered-off, washed with a diluted hydrochloric acid andwater, dried in a vacuum desiccator over P₂ O₅ to give a mixture ofcis-[PtClINH₃ (2-CH₃ -cyclo-C₆ H₁₀ NH₂)] and cis-[PtI₂ NH₃ (2-CH₃-cyclo-C₆ H₁₀ NH₂)]. The yield of the mixture of these complexes is5.28g; the content of platinum is 36.7% the yield as calculated forplatinum is 89%.

The exchange reaction of the resulting mixture of platinumdihalocomplexes with silver S(-)-malate and recovery of the finalproduct are carried out as described in Example 4 hereinbefore.

The yield of the final product is 3.34 g (64% as calculated for K[PtCl₃NH₃ ].

Found, %: Pt 41.9, N 6.0, C 28.5, H 5.1. C₁₁ H₂₃ N₂ O₅.5 Pt. Calculated,%: Pt 41.8, N 6.0, C 28.3, H 5.0.

EXAMPLE 17 Preparation ofS(-)malatoammine(3-methyl-cyclohexylamine)platinum(II)[Pt(S(-)-OOCCH(OH)CH₂ COO)NH₃ (3-CH₃ -cyclo-C₆ H₁₀ NH₂)].0.5H₂ O

The synthesis of this compound is effected in a manner similar to thatdescribed for the compound of Example 16. As the reactant for thepreparation of a mixture of platinum dihalocomplexes3-methylcyclohexylamine is used.

The final product is obtained in the yield of 61% as calculated forK[PtCl₃ NH₃ ].

Found, %: Pt 42.0, N 6.1, C 28.0, H 5.2. C₁₁ H₂₃ N₂ O₅.5 Pt. Calculated,%: Pt 41.8, N 6.0, C 28.3, H 5.0.

EXAMPLE 18 Preparation ofS(-)-malatoammine(4-methylcyclohexylamine)platinum(II)[Pt(S(-)-OOCCH(OH)CH₂ COO)NH₃ (4-CH₃ -cyclo-C₆ H₁₀ NH₂)].0.5H₂ O

The synthesis of this compound is carried out in a manner similar tothat for the compound according to Example 16. As the reactant for thepreparation of a mixture of platinum dihalocomplexes4-methylcyclohexylamine is used.

The final product is obtained in the yield of 65% as calculated forK[PtCl₃ NH₃ ].

Found, %: Pt 42.1, N 5.9, C 27.9, H 5.1. C₁₁ H₂₃ N₂ O₅.5 Pt. Calculated,%: Pt 41.8, N 6.0, C 28.3, H 5.0.

EXAMPLE 19 Preparation ofS(-)-malatoammine(4-hydroxycyclohexylamine)platinum(II)[Pt(S(-)-OOCCH(OH)CH₂ COO)NH₃ (4-OH-cyclo-C₆ H₁₀ NH₂)]. H₂ O

The synthesis of this compound is carried out in a manner similar tothat for the compound described in Example 16 hereinbefore. As thereactant for the preparation of a mixture of platinum dihalocomplexes4-hydroxycyclohexylamine is used.

The final product is obtained in the yield of 58% as calculated forK[PtCl₃ NH₃ ].

Found, %: Pt 40.6, N 5.8, C 25.4, H 4.7. C₁₀ H₂₂ N₂ O₇ Pt. Calculated,%: Pt 40.9, N 5.9, C 25.2, H 4.6.

EXAMPLE 20 Preparation ofmalonatoammine(tetrahydrofurfurylamine)platinum(II) [Pt(OOCCH₂ COO)NH₃(C₄ H₇ OCH₂ NH₂)]

To a solution of 4.00 g of K[PtCl₃ NH₃ ] (11.2 mmol) in about 25 ml ofwater 8.36 g of KI (50.4 mmol, molar ratio of 1:4.5) are added. Thesolution is kept in darkness for 20 minutes and added under stirringwith 1.36 g of tetrahydrofurfurylamine (13.4 mmol) in 5 ml of water. Thereaction mixture is stirred for 5 minutes. The resulting yellow residueis filtered-off, washed with a diluted hydrochloric acid and water driedin a vacuum desiccator over P₂ O₅ to give a mixture of cis-[PtClINH₃ (C₄H₇ OCH₂ NH₂)] and cis-[PtI₂ NH₃ (C₄ H₇ OCH₂ NH₂)].

The yield of the mixture of these complexes is 4.91 g; the content ofplatinum is 40.7%, the yield as calculated for platinum is 91.5%.

To 4.60 g of the mixture of these platinum complexes (9.60 mmol)suspended in about 70 ml of water 3.05 g of silver malonate (9.60 mmol)are added. The reaction mixture is stirred in darkness upon heating tothe temperature of 40° C. for 6 hours. The precipitated mixture of AgCland AgI is filtered-off. The filtrate is intermixed with activatedcarbon. After separation of the latter by filtration the filtrate isevaporated in vacuum and the final product is precipitated by theaddition of ethanol and acetone. The precipitated substance is washedwith dry ether and dried in a vacuum desiccator over P₂ O₅. The productyield is 3.16 g or 68% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 46.6, N 6.6, C 23.4, H 4.0. C₈ H₁₆ N₂ O₅ Pt. Calculated, %:Pt 47.0, N 6.8, C 23.1, H 3.9.

EXAMPLE 21 Preparation ofS(-)-malatoammine(tetrahydrofurfurylamine)platinum(II)[Pt(S(-)-OOCH(OH)CH₂ COO)NH₃ (C₄ H₇ OCH₂ NH₂)].H₂ O

The synthesis of this compound is carried out in a manner similar tothat of the compound described in the foregoing Example 20. SilverS(-)-malate is entered into an exchange reaction with a mixture ofplatinum dihalocomplexes. The final product is obtained in the yield of59% as calculated for K[PtCl₃ NH₃ ].

Found, %: Pt 41.6, N 5.9, C 23.9, H 4.1. C₉ H₁₀ N₂ O₇ Pt. Calculated, %:Pt 42.1, N 6.0, C 23.3, H 4.4.

The antitumor activity of the compounds according to the presentinvention has been studied on a number of strains of grafted solidtumors and leukosises of mice: plasmacytoma MOPC-406, lymphoid leukosisL-1210, hemocytoblastosis La, hepatoma 22a, mammal adenocarcinoma Ca755.

As the criteria for the antitumor activity for leukosises and ascyticforms of tumors the increase of the lifespan of treated animals (ILS, %)

    ILS%=T-C/C·100,

wherein:

T--average lifespan of treated animals;

C--average lifespan of control animals;

and for a solid tumor--tumor growth inhibition (TGI, %)

    TGI5=O-K/K·100,

wherein:

O--volume of tumors in the group of treated animals;

K--volume of tumors in the control group were employed.

The experiments were carried out on line mice and their hybrides of thefirst generation. For the purpose of comparison, simultaneously studiedwas the antitumor activity of cis-dichlorodiammineplatinum(II) (DDP).The compounds were administered to animals intraperitoneally in a 5%solution of glucose once or daily over 5 days within the time limitsadopted in experimental studies of corresponding tumors. DDP wasadministered in the same manner in a 0.9% solution of NaCl. The resultsobtained in these comparative experiments are represent in Table 1hereinbelow.

                                      TABLE 1                                     __________________________________________________________________________    Antitumor activity of mixed platinum carboxylatocomplexes (II)                                        Optimal                                                                       dose       Increase of lifespan,                                                                             Tumor growth                                   range,                                                                             Days of                                                                             Hepato-             inhibition, %          No.                                                                              Compound             mg/kg                                                                              treatment                                                                           ma 22a                                                                             L-1210                                                                            La  MOPC-406                                                                             Ca-755                 1  2                    3    4     5    6   7   8      9                      __________________________________________________________________________    1. Malonatoammine(cyclopropylamine)-                                                                  60-70                                                                              2     --    48 --  177(1/6)                         platinum(II) of Example 1                                                                          60   7     --   --  --  150(1/6)                                              15-25                                                                              2-6    85(0/6)                                                                            39  29 268(2/6)                                                                             89                     2. (Hydroxymalonato)ammine(cyclobutyl-                                                                60   2     --    71 --  --     --                        amine)platinum(II) of Example 3                                                                    25   2-6   --   100 --  --                                                    20   2-6   --   --  --  --     70                     3. Malonatoammine(cyclopentylamine)-                                                                  40-60                                                                              2     --    45 --  300(5/6)                         platinum(II) of Example 6                                                                          50   7     --   --  --  329(3/6)                                              15-25                                                                              2-6   140(2/6)                                                                            36  21 286(3/6)                                                                             76                     4. S(-)-Malatoammine(cyclopentylamine)-                                                               60-80                                                                              2     --   101 --  310(5/6)                         platinum(II) of Example 4                                                                          20    7-11 --   --  --  356(3/6)                                              15-25                                                                              2-6   225(4/6)                                                                           195 113 327(6/6)                                                                             96                     5. RS--Malatoammine(cyclopentylamine)-                                                                20-25                                                                              2-6   322(2/6)                                                                           156 --  350(4/6)                                                                             95                        platinum(II) of Example 5                                                  6. Succinatoammine(cyclohexylamine)-                                                                  150  2     --   120 --                                   platinum(II) of Example 15                                                                         30   2-6   --   108 --  --     72                     7. S(-)-Malatoammine(tetrahydrofurfuryl-                                                              20-40                                                                              2-6   340(2/6)                                                                           120 --  280(3/6)                                                                             95                        amine)platinum(II) of Example 21                                           8. Cis-Dichlorodiammineplatinum(II)/                                                                   3   1-5        116 --  --                               prior art compound (DDP)/                                                                           8   1     --   --  200 --                                                     2   2-5   --   --  --  140(0/6)                                               5   3     120(0/6)                                                                           --  --  --                                                     8   2     --   --  --  --     95                     __________________________________________________________________________     Note:                                                                         Shown in brackets is the number of cured animals divided by the number of     animals employed for the experiment. Symbol (-) defines that no experimen     was carried out.                                                         

As it follows from the Table, all the compounds according to the presentinvention exhibit a strong antitumor effect. The latter is revealed in aconsiderable increase of the lifespan of mice with leukosis L-1210,MOPG-406, hepatoma 22a and in a strong inhibition of growth of a solidtumor adenocarcinoma Ca-755. Furthermore, the compound of Example 4considerably extends the lifespan of animals with hemocytoblastosis La.It should be noted that compounds of Examples 1, 4, 6, 5, 21 ensurecuring of a certain number of animals (up to 100%) in the case ofplasmocytoma MOPC-406, while compounds of Examples 4, 6, 5, 21 cure aportion of animals with hepatoma 22a. In experiments with DDP no curingof animals with these tumors is observed. Maximum tolerable doses of allthe complexes tested are considerably higher as compared to DDP whichpoints to their lower molar toxicity. The maximum tolerable doses of asingle-time administration are within the range of from 50 to 150 mg/kg(for DDP-8 mg/kg), for a 5-days' treatment course-20-40 mg/kg (for DDP-3mg/kg).

Therefore, the compounds according to the present invention feature ahigh antitumor activity and have their specific characteristics of theantitumor effect.

It should be also noted that an important advantage of the compoundsaccording to the present invention is their high solubility in water andaqueous solution employed for injections, whereas the majority of knownplatinum complexes revealing an antitumor activity are sparingly solubleor substantially insoluble in water.

INDUSTRIAL APPLICABILITY OF THE INVENTION

The mixed platinum carboxylatocomplexes according to the presentinvention can be useful in pharmaceutical industry for the preparation,on their basis, of pharmaceutical compositions employed in medicine forthe treatment of malignant tumors and leukosises.

We claim:
 1. Platinum(II) carboxylatocomplexes of the formula: ##STR7##wherein R is tetrahydrofurfuryl or a cyclo-C_(n) R"_(2n-1), each R" isindependently H, an alkyl, or hydroxyl, n=3-6, R' is --CH₂ --, --CH₂--CH₂ --, CH(OH)--, --CH(OH)--CH₂ --, or --CH(OH)--CH(OH)--.
 2. Aplatinum(II) carboxylatocomplex according to claim 1, characterized inthat in the general formula R is cyclo-C₅ H₉ and R' is --CH(OH)--CH₂ --.3. A platinum(II) carboxylatocomplex according to claim 1, characterizedin that in the formula R is ##STR8## and R' is --CH(OH)--CH₂ --.
 4. Aplatinum(II) carboxylatocomplex according to claim 1, characterized inthat in the formula R is cyclo-C₅ H₉ and R' is --CH₂ --.